Indanyloxyphenylcyclopropanecarboxylic acids

a technology of indanyloxyphenylcyclopropanecarboxylic acids and cyclopropanecarboxylic acids, which is applied in the field of new drugs, can solve the problems of diabetes, impaired beta cell function, and increased blood glucose levels, and achieves the effects of reducing the risk of cardiovascular diseas

Active Publication Date: 2015-05-28
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]GPR40 modulators are known in the art, for example, the compounds disclosed in WO 2004041266 (EP 1559422), WO 2007033002 and WO 2009157418. The indanyloxyphenylcyclopropanecarboxylic acids of the present invention may provide several advantages, such as enhanced potency, high metabolic and / or chemical stability, high selectivity and tolerability, enhanced solubility, and the possibility to form stable salts.SUMMARY OF THE INVENTION

Problems solved by technology

The amount of insulin produced by the remaining pancreatic islet cells is too low, resulting in elevated blood glucose levels (hyperglycemia).
High blood glucose levels (and also high blood lipid levels) in turn lead to an impairment of beta cell function and to an increase in beta cell apoptosis.
Diabetes is a very disabling disease, because today's common antidiabetic drugs do not control blood sugar levels well enough to completely prevent the occurrence of high and low blood sugar levels.
Out of range blood sugar levels are toxic and cause long-term complications for example retinopathy, renopathy, neuropathy and peripheral vascular disease.
Obesity is associated with an increased risk of follow-up diseases such as cardiovascular diseases, hypertension, diabetes, hyperlipidemia and an increased mortality.
These often occur in the same patients and are major risk factors for development of diabetes type II and cardiovascular disease.

Method used

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  • Indanyloxyphenylcyclopropanecarboxylic acids
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  • Indanyloxyphenylcyclopropanecarboxylic acids

Examples

Experimental program
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examples / preliminary remarks

EXAMPLES / PRELIMINARY REMARKS

[0252]The terms “ambient temperature” and “room temperature” are used interchangeably and designate a temperature of about 20° C. As a rule, 1H-NMR and / or mass spectra have been obtained for the compounds prepared.

Analytical Methods

[0253]1H-NMR spectra were recorded at 25° C. on a Varian INOVA (500 MHz) spectrometer or a Varian (400 MHz) spectrometer.

GC (Method 1):

[0254]Instrument: GC / MS Thermo Scientific TRACE GC ULTRA, DSQ II MS single quadrupole[0255]Column: Agilent DB-5MS, 25 m x 0.25 mm×0.25 um[0256]Carrier gas: Helium, 1 mL / min constant flow[0257]Oven Program: 50° C., to 100° C. in 10° C. / min, to 200° C. in 20° C. / min, to 320° C. in 30° C. / min (hold 10 min).[0258]Detection: DSQ II MS single quadrupole[0259]Ion source: EI[0260]Scan range: 50-450 amu

LC (Method 2):

[0261]Instrument: LC / MS ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole[0262]Column: Synergi Hydro RP100A, 2.5 μm, 3×50 mm[0263]Mobile phase: A=H2O 90%+10% CH3CN+NH4COOH 10 mM[0264]B═...

example 45

(1S,2S)-2-[4-((R)-7-Fluoro-4-phenoxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid

[0458]

[0459](1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 150 mg, 0.42 mmol), pyridine (dry; 0.133 mL, 1.68 mmol) and phenylboronic acid (308 mg, 2.53 mmol) are suspended in dichloromethane (10 mL), 4 Å molecular sieves and copper(II)acetate (153 mg, 1.52 mmol) are added and the mixture is stirred under oxygen atmosphere at room temperature for 20 h. NH4OH (2 M aqueous solution, 20 mL) is added and the mixture is extracted with dichloromethane. The organic phase is collected, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by flash chromatography (10-100% ethyl acetate in cyclohexane) to give the title compound (Yield: 40 mg). LC (METHOD 9): tR=2.52 min; Mass spectrum (ES+): m / z=405 [M+H]+.

example 46

(1S,2S)-2-{4-[(R)-5-Cyano-4-(6-methoxy-pyridin-3-ylmethyl)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid

[0460]

[0461](1S,2S)-2-{4-[(R)-4-(6-Chloro-pyridin-3-ylmethyl)-5-cyano-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid (Example 40, 100 mg, 0.22 mmol) is suspended in methanol (10 mL) and sodium hydride (60% in mineral oil, 27 mg, 0.67 mmol) is added. After 6 hours at 90° C. sodium methoxide (130 mg, 2.25 mmol) is added and the mixture stirred for 24 hours at 90° C. The solvent is removed under vacuum and the residue is purified by flash chromatography (0-10% MeOH in CH2Cl2) to give the title compound (Yield: 13 mg). LC (METHOD 3): tR=4.04 min; Mass spectrum (ES+): m / z=441 [M+H]+.

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Abstract

A compound of formula I,wherein the groups R1, R2, R3, X, m, and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2. Furthermore, the invention relates to novel intermediates, useful for the synthesis of compounds of formula I.

Description

FIELD OF THE INVENTION[0001]The present invention relates to novel indanyloxyphenylcyclopropanecarboxylic acids, that are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR 1), to processes for their preparation, to pharmaceutical compositions containing these compounds and to their medical use for the prophylaxis and / or treatment of diseases which can be influenced by the modulation of the function of GPR40. Particularly, the pharmaceutical compositions of the invention are suitable for the prophylaxis and / or therapy of metabolic diseases, such as diabetes, more specifically type 2 diabetes mellitus, and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.BACKGROUND OF THE INVENTION[0002]Metabolic diseases are diseases caused by an abnormal metabolic process and may either be congenital due to an inherited enzyme abnormality or acquired due to a disease of an endocrine ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C62/12A61K45/06C07D309/10A61K31/351C07D309/12C07C317/18C07D295/155A61K31/5375C07C65/26A61K31/194C07C235/46A61K31/195C07C235/48C07D309/14C07D295/192C07C255/54A61K31/277A61K31/192
CPCC07C62/12C07C2102/08A61K45/06C07D309/10A61K31/351C07D309/12C07C317/18C07D295/155A61K31/5375C07C65/26A61K31/194C07C235/46A61K31/195C07C235/48C07D309/14C07D295/192C07C255/54A61K31/277A61K31/192A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P43/00C07C62/34C07C317/22C07D213/61C07D213/62C07D213/64C07D215/20C07D231/12C07D231/56C07D249/08C07D257/04C07D271/06C07D277/64C07D295/088C07D295/18C07C2601/02C07C2602/08C07C2602/02
Inventor LINGARD, IAINHAMPRECHT, DIETER
Owner BOEHRINGER INGELHEIM INT GMBH
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